QUANTIFICATION OF THE CALCIUM ANTAGONISM OF LACIDIPINE BY KINETIC-ANALYSIS

The calcium antagonist activity of the long-acting 1,4-dihydropyridine (DHP) lacidipine has been analyzed in rabbit basilar artery using a w ashout design in constant depolarizing conditions. From the kinetics o f the loss of effect with washing, it was possible to fit a model that included the rate constant for dissociation of the DHP from the membr ane (k(-1)) together with its affinity for the voltage-activated chann el (K-2) The k(-1) values for lacidipine and two other DHPs (amlodipin e and nifedipine) have been calculated as 0.0098, 0.0182 and 0.166 min (-1), respectively. Assuming that the externally applied concentration of the DHP reflected the concentration in the membrane, the apparent pK(2) values of 9.80, 9.0 and 9.25 were calculated for the three calci um antagonists. These values are in good agreement with those estimate d in a previous study. When the partition of lacidipine into the membr ane was taken into consideration, its apparent pK(2) was reduced to 4. 85. Thus, the study reinforces the concept that the high membrane part ition of lacidipine contributes not only to its duration of action but also to its very high potency.